The present invention relates to variously-substituted 2-amino-2-phenyl-alkanol derivatives which are particularly useful especially for their analgesic action. The present invention also relates to the preparation of these derivatives as well as the pharmaceutical compositions containing them.
(S) 2-methylamino-2-phenyl-n.butyl 3,4,5-trimethoxy benzoate and its use in the treatment of chronic pain have been described in international application WO 99/01417. The use of trimebutine 2-dimethylamino-2-phenylbutyl-3,4,5-trimethoxy-benzoate hydrogen maleate or its stereoisomers in the treatment of inflammatory disorders and pain have been described in European application EP 1,110,549. Esters of amino alcohols with the following structure have been described in UK Patent Application GB 1,434,826:
in which R1 to R3 can be in particular a hydrogen atom, R4 can be an alkyl radical, R7 can be aryl optionally substituted by 1 to 3 alkoxy radicals and R5 and R6 represent a hydrogen atom, an alkyl or aralkyl radical or form a heterocycle together with the nitrogen atom to which they are attached. The products are useful as anti-spasmodic agents. The UK application also describes carbamates for which R7 has the structure —NH—R″7. The arylcarbamates thus constituted have analgesic and anti-inflammatory activity. However, the modifications made to the amine were quite limited and were unable to lead to powerful analgesics.
It has now been found that 2-amino-2-phenyl-alkanol ester derivatives of general formula:
in which:    R1 is a hydrogen atom, an alkyl radical containing 1 to 4 carbon atoms in a straight or branched chain, an alkyl radical containing 2 to 4C in a straight or branched chain substituted by hydroxy, alkoxy, alkylthio, acyloxy, amino, alkylamino, dialkylamino, alkylcarbarnoyloxy, alkoxycarbonylamino, ureido or alkylureido,    R2 is a —CO—R radical in which R is a hydrogen atom, an alkyl radical, an aryl, heterocyclyl, benzyl or heterocyclylmethyl radical,    a —CO—Y—R4 radical for which Y is a heteroatom chosen from —O—, —S—, —NH—, -Nalk- for which alk is a straight or branched alkyl radical containing 1 to 4C, and R4 is chosen from the alkyl, aryl, aralkyl or heterocyclylalkyl radicals, capable of being substituted by one or more halogen atoms or hydroxy, alkyl radicals containing from 1 to 4 C in a straight or branched chain, alkoxy, alkylthio, acylaminoalkylthio, alkoxycarbonyl or acylamino the alkyl residues of which contain 1 to 4C in a straight or branched chain, or oxo, or capable of being substituted by an R5COO-radical in which R5 is an alkyl radical optionally substituted by benzyloxycarbonylamino, acylamino or by an amino acid residue, or represents an heterocyclyl radical, or    R2 is an alkyl radical containing 2 to 4C substituted by hydroxy, alkoxy, alkylthio, acyloxy, amino, alkylamino, dialkylamino the alkyl residues of which can form, with the nitrogen atom to which they are attached, a heterocycle having 5 or 6 members, optionally bearing another heteroatom chosen from oxygen or nitrogen, or substituted by alkylcarbamoyloxy, alkoxycarbonylamino, ureido or alkylureido, it being understood that said substituted alkyl radical is in a straight or branched chain and comprises at least 2 carbon atoms between the nitrogen atom bearing R2 and the substituent;    R3 is an alkyl radical containing 1 to 4 carbon atoms in a straight or branched chain, in their R or S forms or their mixtures, as well as their pharmaceutically acceptable salts, when these exist, have a particularly useful activity as analgesics, in particular in the treatment of chronic pain.
It is understood that unless specifically mentioned, the alkyl or acyl radicals or residues are straight or branched and contain 1 to 7 carbon atoms, in particular the acyl radicals can be acetyl radicals. The aryl or aralkyl radicals can be mono or bicyclic radicals, comprising 6 to 10 members, for example phenyl, naphthyl, benzyl, phenethyl or naphthylalkyl. It is understood that the heterocyclyl radicals can be mono or bicyclic radicals, aromatic or not, comprising 5 to 10 members and containing 1 to 4 heteroatoms chosen from oxygen, nitrogen or sulphur. In particular they can be chosen from thienyl, furyl, pyrrolyl, pyrrolidinyl piperidyl pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, piperazinyl, dioxolyl, imidazolyl, imidazolinyl, pyrazolyl, tetrazolyl, pyrannyl, tetrahydropyrannyl, tetrahydrofuranyl, oxazolyl, thiazolyl, thiazinyl, morpholinyl, thiomorpholinyl, indolyl, indolizinyl, quinolyl, naphthyridinyl radicals. It is understood that the amino acids mentioned above can be in particular chosen from glycine, alanine, leucine, isoleucine, proline, valine, phenylalanine in the L or D series and that these groups are protected prior to the synthesis reactions, in the form of amides or carbamates; the protection and the release of the protective radicals is carried out according to the methods described by T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 4th Edition ISBN 978-0-471-69754-1, December 2006. The halogen atoms are chosen from chlorine, fluorine, bromine and iodine.
According to a preferred embodiment of the invention, the alkyl or acyl radicals are straight or branched and contain 1 to 4 carbon atoms. According to the invention, the 2-amino-2-phenyl-alkanol ester derivatives of general formula (I) are prepared by the action of a derivative of general formula:
in which Z is a halogen atom, a hydroxy radical or the residue of a reactive ester, on the derivative of 2-amino-2-phenyl alkanol of general formula:
in which R1 and R3 are defined as previously and R′2 is a hydrogen atom or is defined as R2 previously, followed if appropriate, when one of R′2 or R1 is the hydrogen atom, by substitution of the amine of the 2-amino-2-phenyl-alkanol ester derivative obtained, of general formula:
in which R1 and R′2 and R3 are defined as above.                either, when R′2 is H, and if it is desired to obtain derivatives for which R2 is —CO—R, by the action of a reactive derivative of the acid of general formulaR—COOH  (V)                    in which R is defined as previously,                        or, when R′2 is H, and it is desired to obtain derivatives for which R2 is —CO—Y—R4, Y being O, S, NH or Nalk                    either, by the action of phosgene, followed by the reaction with the alcohol, the thiol or the amine of general formula:R4—YH  (VI)                            in which R4 is an optionally-substituted alkyl radical and where if appropriate the functions which can be altered in the reaction are previously protected, or an aryl, aralkyl or heterocyclylalkyl radical, and Y is the oxygen or sulphur atom, or a NH or Nalk radical                                    or, by the action of the halide of general formula:R4—Y—COHal  (VII)            in which R4 is defined as previously, preferably branched aryl or alkyl, Y is the oxygen or sulphur atom and Hal is a halogen atom, preferably chlorine,            or, when it is desired to obtain an R4 radical bearing the —C(alk)-O—CO—R5 substitution for which alk is defined as in claim 2 and R5 is defined as in claim 1, by the action of chloroalkylchloroformate, followed by reacting the product obtained with an alkaline salt of the corresponding acid R5COOH, for example the sodium salt, potassium salt or the caesium salt of the corresponding acid: R5COOCs, or alternatively the silver salt or the quaternary ammonium salt (for instance the tert-butyl ammonium salt) of said acid.                        either, when R′2 is H, and if it is desired to obtain derivatives for which R2 is substituted alkyl, or when a derivative of general formula (IV) has been obtained, for which R1 is a hydrogen atom and R′2 is defined as R2, and if it is desired to obtain a product of general formula (I) for which R1 is alkyl optionally substituted, by acylation by an acid halide or a reactive ester of structure:R2—CO-Z  (VIIIa)orR1—CO-Z  (VIIb)                    in which R1 or R2 are defined as above and Z is a halogen atom or the residue of a reactive ester, followed by reducing the amide formed to an amine.                        or also, when a derivative of general formula (IV) has been obtained for which R1 is a hydrogen atom and R′2 is defined as R2, and if it is desired to obtain a product of general formula (I) for which R1 is alkyl, by the action of a halogenated derivative of formulaR1—X  (IX)                    in which R1 is an alkyl radical and X is a halogen atom or a sulphonic radical, in the presence of a base.                        
The product of general formula (II) can be a reactive 3,4,5-trimethoxy benzoic acid derivative, such as an acid halide or a reactive ester. The reaction of the 2-amino-2-phenyl alkanol derivative of general formula (II) is carried out preferably using a derivative for which R′2 is the hydrogen atom. When the product of general formula (II) is a reactive derivative of 3,4,5-trimethoxy benzoic acid such as the acid halide or a reactive ester, the reaction of the derivative of general formula (II) with the 2-amino-2-phenyl alkanol derivative of general formula (III) is carried out advantageously in the presence of a nitrogenous base such as for example triethylamine, dimethylaminopyridine, diisopropylethylamine in the case of the acid halide of formula (II) and the reaction is generally carried out in an organic solvent such as a chlorinated solvent (dichloromethane, dichlorethane, chloroform for example), at a temperature comprised between 0 and 70° C., preferably operating under nitrogen. And in the case of a reactive ester of formula (II), in the presence of sodium methylate in an organic solvent such as toluene in the presence of an alcohol such as methanol or ethanol, at a temperature comprised between 25 and 150° C.
When Z is a halogen atom, it is advantageously chosen from chlorine or bromine. When the product of general formula (II) is 3,4,5-trimethoxy benzoic acid, the reaction is generally carried out in the presence of a carbodiimide, in a halogenated solvent (dichloromethane, dichlorethane, chloroform for example), at a temperature comprised between 0 and 70° C. It is understood that when it is desired to obtain a derivative of general formula (IV) in R or S form, a derivative of 2-amino-2-phenyl alkanol of general formula (III) in R or S form is reacted. It is also understood that the derivatives of general formula (IV) in R or S form lead to derivatives of general formula (I) in R or S form.
The substitution of the amine of the derivative of general formula (IV) by the action of a reactive derivative of the acid of general formula (V) is advantageously carried out using the acid halide or an ester, in particular reactive ester, preferably in the presence of a condensation agent such as a tertiary amine (triethylamine, diisopropylethylamine, dimethylaminopyridine in particular). The reaction is generally carried out in an organic solvent such as a chlorinated solvent (dichloromethane, dichlorethane, chloroform for example), at a temperature comprised between 0 and 70° C. When it is desired to obtain the derivative for which R2 is formyl, the operation is advantageously carried out by the action of an ester, dispensing with the use of a solvent.
The reaction of the alcohol or thiol of general formula (VI) is carried out after the action of phosgene on the amine of the derivative of general formula (IV), (in the form of a solution in an aromatic solvent such as for example toluene), in an organic solvent such as a halogenated solvent (for example chlorinated solvent such as dichloromethane, dichlorethane or chloroform) in the presence of a tertiary amine (triethylamine, diisopropylethylamine, dimethylaminopyridine in particular) at a temperature comprised between 0 and 25° C. The reaction of the alcohol or the thiol of general formula (VI) is carried out by the addition of the derivative of general formula (VI) in the presence of a tertiary amine as mentioned above, at a temperature comprised between 0 and 70° C., in a halogenated solvent (dichloromethane, dichlorethane, chloroform for example). Preferably operating under nitrogen. It is understood that when substituents are at risk of being altered during the course of the reaction, the latter are protected beforehand. The protection and release of the protective radicals is carried out according to the methods described by T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 4th Edition ISBN 978-0-471-69754-1, December 2006.
The reaction of the derivative of general formula (VII) with the amine of the derivative of general formula (IV) is carried out in the presence of a condensation agent such as a tertiary amine (triethylamine, diisopropylethylamine, dimethylaminopyridine in particular). The reaction is generally carried out in an organic solvent such as a chlorinated solvent (dichloromethane, dichlorethane, chloroform for example), or tetrahydrofuran, at a temperature comprised between 0 and 70° C. Preferably the operation is carried out under nitrogen. When it is desired to obtain a compound in which the R4 radical have the —C(alk)-O—CO—R5 substitution, the reaction is carried out through the action of the chloroalkylchloroformate on the compound of the general formula (IV), and the reaction is conducted in an organic solvent such as a chlorinated solvent (dichloromethane, dichlorethane for example), or such as an ether (tetrahydrofuran for example), at a temperature of between −10 and 50° C. It is followed by the reaction of the obtained compound with an alkaline salt of the corresponding acid R5COOH, for example the sodium salt, the potassium salt or the caesium salt, the silver salt or the quaternary ammonium salt, in an organic solvent such as, for instance an amide such as dimethylformamide, a chlorinated solvent (dichloromethane for instance), an ester (ethyl acetate for instance), an aromatic hydrocarbon (toluene for example), a nitrile (acetonitrile for example), a ketone (acetone, methyl ethyl ketone for example), optionally in the presence of sodium iodide, at a temperature of between 0 and 60° C.
When it is desired to obtain a compound of the general formula (I) in which R2 is a substituted alkyl or in which R1 is an optionally substituted alkyl, the alkylation reaction of the amine of the derivative of general formula (IV) is carried out in a halogenated solvent (dichloromethane, dichlorethane for example) or in an ether (tetrahydrofuran), at a temperature comprised between 0 and 70° C. If necessary, the reactive ester can be prepared using hydroxybenzotriazole. The reduction is carried out in the presence of borane in tetrahydrofuran, at a temperature comprised between 0 and 70° C. The reaction of the product of formula (IX) is carried out using a halogenated derivative for which the halogen is chosen from chlorine, bromine or iodine or using a sulphonic derivative such as tosylate, mesylate or triflate, in the presence of a base such as an alkaline carbonate (NaHCO3 or KHCO3 for example).
The derivatives of 3,4,5-trimethoxy benzoic acid of general formula (II) can be prepared according to the usual methods for the conversion of carboxylic acids to their reactive derivatives which do not change the remainder of the molecule. The derivatives of general formula (III) can be prepared according to the method described in patent applications FR 2,765,218 or EP 510,168, or by analogy with the method described in these applications. The halogenated derivatives of general formula (VII) can be prepared by the action of phosgene on the corresponding alcohol or thiol of general formula (VI). The operation is carried out under conditions analogous to the conditions described previously for the action of phosgene on the amine of the derivative of general formula (IV). It is understood that when it is desired to obtain a product of general formula (I) in S or R form, a derivative of 2-amino-2-phenyl alkanol of general formula (III) in S or R form is reacted.
The 2-amino-2-phenyl alkanol derivatives of general formula (III) in S or R form can be prepared according to the method described in European patent EP 510,168 or by separation according to the usual methods for the separation of enantiomers which do not affect the remainder of the molecule. When they exist, the pharmaceutically acceptable salts can be addition salts with acids. In particular salts with mineral acids such as for example hydrochlorides, the hydrobromides, sulphates, phosphates or addition salts with organic acids such as for example acetates, maleates, fumarates, tartrates, citrates. The derivatives of general formula (I) can be purified according to the usual methods, in particular by chromatography or by crystallization. The derivatives of general formula (I) are particularly useful due to their powerful analgesic activity, in particular in chronic pain. Their activity has been demonstrated in vitro in the test of the inhibition of the sodium channels by application of the method of G. B. Brown, 3H-batrachotoxinin-A benzoate binding to voltage-sensitive sodium channels: inhibition by the channel blockers tetrodotoxin and saxitoxin, J. Neurosci., 6, 2064 (1986). In vitro in this test, the products according to the invention have demonstrated inhibition activities between 25 and 90% for concentrations of 3.2 (M).
Moreover, in vivo their activity has been demonstrated in the rat in the test of formalin-induced short- and long-phase pain, adapted from the method of Wheeler-Aceto et al., psychopharmacology, 104, 35-44 (1991). In this method the product of Example 4 demonstrated short- and long-phase activity at the dose of 39.3 mg/kg by subcutaneous route. In vivo activity has also been demonstrated in the abdominal pain test, by irritation and distension of the colon in rats according to the method adapted from the method described by Langlois et al., Euro. J. Pharmacol., 324, 211-217 (1997). In this test the product of Example 4 demonstrated activity in rats from 13.1 mg/kg and at doses of 26.2 mg/kg by subcutaneous route. Furthermore, it has been demonstrated, after i.v. injection in rats, that the half-life times of certain products according to the present invention are particularly high. Finally, the products according to the invention do not show toxicity. In fact, in the mouse by intraperitoneal route at doses of 26.2 mg/kg in 7 administrations repeated over 2 days and in the rat by oral route at 39.3 mg/kg, no mortality and no sign of abnormal behaviour were observed.